WO1998030543A1 - Intermediaires de l'endotheline obtenus par reaction d'addition d'un conjugue asymetrique effectuee au moyen d'un additif chiral - Google Patents

Intermediaires de l'endotheline obtenus par reaction d'addition d'un conjugue asymetrique effectuee au moyen d'un additif chiral Download PDF

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WO1998030543A1
WO1998030543A1 PCT/US1998/000263 US9800263W WO9830543A1 WO 1998030543 A1 WO1998030543 A1 WO 1998030543A1 US 9800263 W US9800263 W US 9800263W WO 9830543 A1 WO9830543 A1 WO 9830543A1
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alkyl
aryl
cycloalkyl
group
alkenyl
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PCT/US1998/000263
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English (en)
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Richard D. Tillyer
Feng Xu
David M. Tschaen
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Merck & Co., Inc.
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Priority claimed from GBGB9705858.0A external-priority patent/GB9705858D0/en
Priority to EP98902416A priority Critical patent/EP0973742A1/fr
Priority to EA199900661A priority patent/EA002056B1/ru
Priority to CA002277161A priority patent/CA2277161A1/fr
Priority to HU0001921A priority patent/HUP0001921A3/hu
Priority to SK934-99A priority patent/SK93499A3/sk
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to PL98334318A priority patent/PL334318A1/xx
Priority to NZ336220A priority patent/NZ336220A/xx
Priority to BR9806875-0A priority patent/BR9806875A/pt
Priority to JP10531063A priority patent/JP2000507969A/ja
Priority to AU59089/98A priority patent/AU728441B2/en
Publication of WO1998030543A1 publication Critical patent/WO1998030543A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/48—Aldehydo radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to novel key intermediates in the synthesis of an endothelin antagonist and the method for preparing these key intermediates of formula I.
  • the compound possessing a high affinity for at least one of two receptor subtypes are responsible for the dilation of smooth muscle, such as blood vessels or in the trachea.
  • the endothelin antagonist compounds provide a potentially new therapeutic target, particularly for the treatment of hypertension, pulmonary hypertension, Raynaud's disease, acute renal failure, myocardial infarction, angina pectoris, cerebral infarction, cerebral vasospasm, arteriosclerosis, asthma, gastric ulcer, diabetes, restenosis, prostatauxe endotoxin shock, endotoxin-induced multiple organ failure or disseminated intravascular coagulation, and/or cyclosporin-induced renal failure or hypertension.
  • Endothelin is a polypeptide composed of amino acids, and it is produced by vascular endothelial cells of human or pig. Endothelin has a potent vasoconstrictor effect and a sustained and potent pressor action (Nature, 332, 41 1-415 (1988)).
  • endothelin- 1 endothelin-2 and endothelin-3
  • endothelin-2 endothelin-2 and endothelin-3
  • vasoconstriction and pressor effects Proc. Natl. Acad, Sci, USA, 86, 2863-2867 (1989)
  • the endothelin levels are clearly elevated in the blood of patients with essential hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's disease, diabetes or atherosclerosis, or in the washing fluids of the respiratory tract or the blood of patients with asthmaticus as compared with normal levels (Japan, J. Hypertension, V2, 79, (1989), J. Vascular medicine Biology, 2, 207 ( 1990), Diabetologia, 33, 306-310 (1990), J. Am. Med. Association, 264, 2868 (1990), and The Lancet, ii, 747-748 (1989 ) and ii, 1144-1147 (1990)).
  • endothelin is secreted not only by endothelial cells but also by tracheal epithelial cells or by kidney cells (FEBS Letters, 255, 129-132 (1989), and FEBS Letters, 249, 42-46 (1989)).
  • Endothelin was also found to control the release of physiologically active endogenous substances such as renin, atrial natriuretic peptide, endothelium-derived relaxing factor (EDRF), thromboxane A2, prostacyclin, noradrenaline, angiotensin II and substance P (Biochem. Biophys, Res. Commun., 157. 1164-1168 (1988); Biochem. Biophys, Res. Commun., J ⁇ 5, 20 167- 172 (1989); Proc. Natl. Acad. Sci. USA, 85 1 9797-9800 (1989); J. Cardiovasc. Pharmacol., J_3, S89-S92 (1989); Japan. J.
  • endothelin receptors are present in a high density not only in the peripheral tissues but also in the central nervous system, and the cerebral administration of endothelin induces a behavioral change in animals, endothelin is likely to play an important role for controlling nervous functions (Neuroscience Letters, 97, 276- 279 (1989)). Particularly, endothelin is suggested to be one of mediators for pain (Life Sciences, 49, PL61-PL65 (1991)).
  • endotoxin is one of potential candidates to promote the release of endothelin. Remarkable elevation of the endothelin levels in the blood or in the culture supernatant of endothelial cells was observed when endotoxin was exogenously administered to animals or added to the culture endothelial cells, respectively.
  • endothelin Such various effects of endothelin are caused by the binding of endothelin to endothelin receptors widely distributed in many tissues (Am. J. Physiol., 256, R856-R866 (1989)). It is known that vasoconstriction by the endothelins is caused via at least two subtypes of endothelin receptors (J. Cardiovasc. Pharmacol., 17(Suppl.7 . S119-SI21 (1991)). One of the endothelin receptors is ETA receptor Selective to ET-1 rather than ET-3, and the other is ET ⁇ receptor equally active to ET-1 and ET-3. These receptor proteins are reported to be different from each other (Nature, 348. 730- 735 (1990)).
  • endothelin receptors are differently distributed in tissues. It is known that the ETA receptor is present mainly in cardiovascular tissues, whereas the ET ⁇ receptor is widely distributed in various tissues such as brain, kidney, lung, heart and vascular tissues.
  • Substances which specifically inhibit the binding of endothelin to the endothelin receptors are believed to antagonize various pharmacological activities of endothelin and to be useful as a drug in a wide field. Since the action of the endothelins is caused via not only the ETA receptor but also the ET ⁇ receptor, novel non-peptidic substances with ET receptor antagonistic activity to either receptor subtype are desired to block activities of the endothelins effectively in various diseases.
  • Endothelin is an endogenous substance which directly or indirectly (by controlling liberation of various endogenous substances) induces sustained contraction or relaxation of vascular or non-vascular smooth muscles, and its excess production or excess secretion is believed to be one of pathogeneses for hypertension, pulmonary hypertension, Raynaud's disease, bronchial asthma, gastric ulcer, diabetes, arteriosclerosis, restenosis, acute renal failure, myocardial infarction, angina pectoris, cerebral vasospasm and cerebral infarction.
  • endothelin serves as an important mediator involved in diseases such as restenosis, prostatauxe, endotoxin shock, endotoxin- induced multiple organ failure or disseminated intravascular coagulation, and cyclosporin-induced renal failure or hypertension.
  • EP 0526708 Al and WO 93/08799 Al are representative examples of patent applications disclosing non-peptidic compounds with alleged activity as endothelin receptor antagonists.
  • the present invention discloses an asymmetric conjugate addition for preparing the compound of Formula I,
  • R 1 is: Cl-C ⁇ alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, aryl, or heteroaryl;
  • R is C1-C8 alkyl
  • R 5 is: C 1-C8 alkyl, or aryl.
  • the instant invention relates to a process for the preparation of a compound of formula I:
  • C3-C8 cycloalkyl are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, N(R 5 )2, -C8 alkoxy, C3-C8 cycloalkyl, CO(CH2) n CH3, and
  • aryl is defined as phenyl or naphthyl , which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, N(R5)2, C l -C8 alkoxy, C l -C_ alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2) n CH3, CO(CH2)nCH2N(R 5 )2, and when two substituents are located on adjacent carbons they can join to form a 5- or 6- membered ring with one, two or three heteroatoms selected from O, N, and S, which is unsubstituted or substituted with with one, two or three substituents selected from the group consisting of: H, OH, CO2R 6 , Br, Cl, F, I, CF3, N(R?)2, C1-C8 al
  • Rl is: a) C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, b) aryl, or c) heteroaryl;
  • heteroaryl is defined as a 5- or 6-membered aromatic ring containing 1 , 2 or 3 heteroatoms selected from O, N and S , which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH,
  • CO2R 4 Br, Cl, F, I, CF3, N(R5)2, C ⁇ -C$ alkoxy, Cl -C ⁇ alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2) n CH2N(R5)2,
  • R 3 is a) H, b) C1-C8 alkyl, c) C1-C8 alkenyl, ) C1-C8 alkynyl, e) C1-C8 alkoxyl, f) C3-C7 cycloalkyl, g) S(0) t R5, h) Br, Cl, F, I, i) aryl, j) heteroaryl,
  • X and Y are independently: O, S, or NR ⁇ ;
  • n 0 to 5;
  • t 0, 1 or 2;
  • R 4 is: C1-C8 alkyl
  • R 5 is: C l-C ⁇ alkyl, or aryl
  • R6, is: H, C1-C8 alkyl, or aryl
  • R7 is: H, C1-C8 alkyl, aryl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, N(R5)2, Cl- C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2) n CH3, CO(CH2) n CH2N(R5) 2; or when two R ⁇ substutients are on the same nitrogen they can join to form a ring of 3 to 6 atom;
  • R A Li an organolithium compound, R A Li, in the presence of a chiral additive and an aprotic solvent at a temperature range of about -78°C to about 0°C.
  • heterocyclyl containing one, two or three double bonds, but at least one double bond and 1 , 2 or 3 heteroatoms selected from O, N and S, the heterocyclyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C02R 4 , Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C 1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl,
  • C3-C8 cycloalkyl are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, N(R5)2, Cl-Cs alkoxy, C3-C8 cycloalkyl, CO(CH2) n CH3, and
  • aryl is defined as phenyl or naphthyl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2) n CH3, CO(CH2)nCH2N(R 5 )2, and when two substituents are located on adjacent carbons they can join to form a 5- or 6- membered ring with one, two or three heteroatoms selected from O, N, and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: H, OH, CO2R 6 , Br, Cl, F, I, CF3, N(R?)2, Cl-C ⁇ alkoxy, Cl-Cs
  • Rl is: a) C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, b) aryl, or c) heteroaryl;
  • heteroaryl is defined as a 5- or 6-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from O, N and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, N(R5)2, -C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl,
  • R 3 is a) H, b) C1-C8 alkyl, c) C1-C8 alkenyl, d) C1-C8 alkynyl, e) C1-C8 alkoxyl, f) C3-C7 cycloalkyl, g) S(0) t R5, h) Br, Cl, F, I, i) aryl, j) heteroaryl,
  • X and Y are independently: O, S, or NR ,
  • n 0 to 5;
  • t 0, 1 or 2;
  • R 4 is C1-C8 alkyl
  • R5 is: C 1-C8 alkyl, or aryl
  • R 6 is: H, C1-C8 alkyl, and aryl
  • R? are independently: H, Cl-C8 alkyl, and aryl, when there are two R7 substituents on a nitrogen they can join to form a 3- through 6-membered ring, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C02R 4 , Br, Cl, F, I, CF3, N(R5)2, Cl-C8 alkoxy, Cl-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2) n CH3,
  • R 1 Li an organolithium compound, R 1 Li, in the presence of a chiral additive and an aprotic solvent at a temperature range of about -78°C to about 0°C.
  • the chiral additive is a chiral compound capable of coordinating with chiral additives, such as a) (-)-sparteine, b) N,N,N' ,N' -tetra(C 1 -C6)-alkyltrans- 1 ,2-diamino- cyclohexane, or
  • R and R9 are independently: H, C1-C6 alkyl, C3-C7 cycloalkyl or aryl, except that R 8 and
  • R9 cannot simultaneously be H; and RlO is C1-C6 alkyl or aryl, are useful in this process. It is understood that the amino alcohol represented by the above noted structure has at least one, and potentially two chiral centers.
  • aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, MTBE (methyl t-butyl ether), toluene, benzene, hexane, pentane, and dioxane. or a mixture of said solvents.
  • the preferred aprotic solvent is toluene.
  • the solvent mixtures useful in this process are: hexane and toluene with a catalytic amount of tetrahydrofuran, and pentane and toluene with a catalytic amount of tetrahydrofuran, preferrably hexane and toluene with a catalytic amount of tetrahydrofuran.
  • Cl-C ⁇ alkoxy Cl-C ⁇ alkyl, C2-C ⁇ alkenyl, C2-C ⁇ alkynyl, or
  • C3-C8 cycloalkyl are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, N(R5)2, Cl-C ⁇ alkoxy,
  • aryl is defined as phenyl or naphthyl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3,
  • Rl is: a) C1-C8 alkyl, C2-C8 alkenyl, C2-C ⁇ alkynyl, C3-C ⁇ cycloalkyl, b) aryl, or c) heteroaryl;
  • heteroaryl is defined as a 5- or 6-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from O, N and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl. F, I, CF3, N(R5)2, Cl-C ⁇ alkoxy, C l -C ⁇ alkyl, C2-C ⁇ alkenyl, C2-C alkynyl, or C3-C cycloalkyl, CO(CH2) n CH3, and CO(CH2) n CH2N(R5) 2 ,
  • R 3 is a) CHO, b) CH(OR )2;
  • n 0 to 5
  • t 0, 1 or 2;
  • X and Y are independently: O, S, or NR ,
  • R 4 is Cl-C ⁇ alkyl
  • R 5 is: Cl-C ⁇ alkyl, or aryl
  • R ⁇ is: H, Cl-C ⁇ alkyl, and aryl
  • R7 are independently: H, Cl-C ⁇ alkyl, and aryl, when there are two R7 substituents on a nitrogen they can join to form a 3- through 6-membered ring, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, N(R 5 )2, C1-C8 alkoxy, Cl-C ⁇ alkyl, C2-C alkenyl, C2-C ⁇ alkynyl, or C3-C8 cycloalkyl, CO(CH2) n CH3,
  • R3 is CH(OR 4 )2; with an organolithium compound, R x Li, in the presence of a chiral additive and an aprotic solvent at a temperature range of about -78°C to about 0°C to give the conjugate adduct; and
  • the chiral additive is a chiral compound capable of coordinating with chiral additives, such as a) (-)-sparteine, b) N,N,N' ,N'-tetra(C l -C6)-alkyltrans- 1 ,2-diamino- cvclohexane, or
  • R and R9 are independently: H, C1-C6 alkyl, C3-C7 cycloalkyl or aryl, except that R ⁇ and R9 cannot simultaneously be H; and R ⁇ 0 is C1-C6 alkyl or aryl, are useful in this process.
  • aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, MTBE (methyl t-butyl ether), toluene, benzene, hexane, pentane. and dioxane. or a mixture of said solvents.
  • the preferred aprotic solvent is toluene.
  • the solvent mixtures useful in this process are: hexane and toluene with a catalytic amount of tetrahydrofuran, and pentane and toluene with a catalytic amount of tetrahydrofuran, preferrably hexane and toluene with a catalytic amount of tetrahydrofuran.
  • the solvent mixtures useful in this process are: hexane and toluene with a catalytic amount of tetrahydrofuran, and pentane and toluene with a catalytic amount of tetrahydrofuran, preferrably hexane and toluene with a catalytic amount of tetrahydrofuran.
  • organolithium compound in the presence of a chiral additive and an aprotic solvent at a temperature range of about -78°C to about -20°C.
  • the chiral additive is a chiral compound capable of coordinating with chiral additives, such as a) (-)-sparteine, b) N,N,N' ,N'-tetra(C 1 -C6)-alkyltrans- 1 ,2-diamino- cyclohexane, or
  • aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether. MTBE (methyl t-butyl ether), toluene, benzene, hexane, pentane, and dioxane, or a mixture of said solvents.
  • MTBE methyl t-butyl ether
  • toluene benzene
  • hexane hexane
  • pentane pentane
  • dioxane or a mixture of said solvents.
  • the solvent mixtures useful in this process are: hexane and toluene with a catalytic amount of tetrahydrofuran, and pentane and toluene with a catalytic amount of tetrahydrofuran, preferrably hexane and toluene with a catalytic amount of tetrahydrofuran.
  • alkyl substituents recited above denote straight and branched chain hydrocarbons of the length specified such as methyl, ethyl, isopropyl, isobutyl, tert-butyl, neopentyl, isopentyl, etc.
  • alkenyl-substituents denote alkyl groups as described above which are modified so that each contains a carbon to carbon double bond such as vinyl, allyl and 2-butenyl.
  • Cycloalkyl denotes rings composed of 3 to 8 methylene groups, each of which may be substituted or unsubstituted with other hydrocarbon substituents, and include for example cyclopropyl, cyclopentyl, cyclohexyl and 4-methylcyclohexyl.
  • the alkoxy substituent represents an alkyl group as described above attached through an oxygen bridge.
  • the heteroaryl substituent represents an carbazolyl, furanyl, thienvl, pyrrolyl, isothiazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridyl, pyrimidyl, purinyl.
  • the heterocyclyl substituent represents a pyridyl, pyrimidyl, thienyl, furanyl. oxazolidinyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, imidazolyl, imidazoldinyl, thiazolidilnyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, or pyrrolidinyl.
  • the protected aldehyde represents an acetal, such as -
  • R ⁇ is CHO
  • Z is a leaving group, such as Br. Cl, I, OTriflyl, OTosyl or OMesyl and R 2 is OR 4 or N(R 5 )2;
  • pyridone 1 is alkylated via its dianion with propyl bromide, and the product is then converted into the bromopyridine 3a using a brominating agent such as PBr3.
  • a brominating agent such as PBr3.
  • DIBAL diisobutyl aluminum hydride
  • the aldehyde then undergoes a Heck reaction with t-butyl acrylate using NaOAc, (allyl)2PdCl2, tri-o-tolylphosphine, toluene, reflux to provide the unsaturated ester 4a in high yield.
  • the unsaturated ester 4a is then treated with an alcohol (R 4 OH) and aqueous acid to give the acetal-acceptor 5a.
  • 1,2-amino indanol is acylated (propionyl choride. K2CO3) to give amide 8, which is then converted into the acetonide 9 (2-methoxypropene, pyridinium p-toluene-sulfonate (PPTS)).
  • Acetonide 9 is then alkylated with the bromide 13, (LiHMDS) to give 14, which is then hydrolyzed (H+, MeOH) to give a mixture of acid and methyl ester 15.
  • Reduction (LAH) of the ester/acid mixture provided the alcohol 16 in high yield and optical purity. Protection of the alcohol 16 (TBSC1, imidazole) provided bromide 17, the precursor to organolithium 17a.
  • Compound 17a and a chiral additive, such as sparteine, are added to the , ⁇ -unsaturated ester 5a at -78° to -50°C. Work up with water affords compounds 6a and 6b. Mixtures of compounds 6a and 6b are treated with TBAF or aqueous acid to deprotect the silylated alcohol or acetal and silylated alcohol.
  • Dissolve product of bromination reaction (MW 239.12, 27.6 mmol, 6.60 g) in 66 mL toluene and cool to -42°C. Slowly add DIBAL (1.5 M in toluene, 2 equ, 37 mL) and age 1 h at -42°C. Add HC1 (2 N, 10 equ, 134 mL) and stir vigorously for 30 min. Dilute with ethyl acetate, separate layers, and wash aqueous with ethyl acetate. Combine organic layers, dry (magnesium sulfate), and concentrate in vacuo to afford 90% (MW 242.11, 6.01 g) of 3.
  • Dissolve 3 (MW 242.11, 24.8 mmol, 6.01 g) in 75 mL toluene. Add sodium acetate (MW 82, 3 equ, 6.13 g), t-butyl acrylate (MW 128.17, d 0.875, 2.5 equ, 9.08 mL), P(o-tolyl)3 (MW 304.38, 10 mol %, 755 mg) and allyl palladium chloride dimer (MW 365.85, 5 mol %, 455 mg). Age at reflux for 24 h. Cool, filter and evaporate in vacuo. Isolate 4a (MW 289.37) by silica gel chromatography (92:8 hexanes:ethyl acetate) in 80% yield (5.74 g).
  • Step A Preparation of 6a and 6b
  • Step B Preparation of 6c and 6 ⁇ (Method A) A solution of 500 mg (0.8 mmol) of above products 6a and
  • Compound 7 is a commericially available starting material, for example, see DSM Andeno, Grubbenvorsterweg 8, P.O. Box 81, 5900 AB Venlo,The Netherlands.
  • Compound 10 is a commericially available starting material, for example, see Lancaster Synthesis, P.O. Box 1000, Windham, NH 03087-9977 or Ryan Scientific, Inc., P.O. Box 845, Isle of Palms, SC 29451-0845.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
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Abstract

L'invention concerne un procédé destiné à un processus de préparation d'un intermédiaire clé, dans la synthèse d'un antagoniste de l'endothéline, cet intermédiaire correspondant à la formule (I) et consistant à utiliser un additif chiral pour induire une addition de conjugué àsymétrique.
PCT/US1998/000263 1997-01-14 1998-01-09 Intermediaires de l'endotheline obtenus par reaction d'addition d'un conjugue asymetrique effectuee au moyen d'un additif chiral WO1998030543A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
AU59089/98A AU728441B2 (en) 1997-01-14 1998-01-09 Endothelin intermediates by asymmetric conjugate addition reaction using a chiral additive
EA199900661A EA002056B1 (ru) 1997-01-14 1998-01-09 Получение промежуточных соединений эндотелина реакцией ассиметрического сопряженного присоединения с использованием хиральной добавки
CA002277161A CA2277161A1 (fr) 1997-01-14 1998-01-09 Intermediaires de l'endotheline obtenus par reaction d'addition d'un conjugue asymetrique effectuee au moyen d'un additif chiral
HU0001921A HUP0001921A3 (en) 1997-03-21 1998-01-09 Endothelin intermediates by asymmetric conjugate addition reaction using a chiral additive
SK934-99A SK93499A3 (en) 1997-01-14 1998-01-09 Process for the preparation of intermediates
EP98902416A EP0973742A1 (fr) 1997-01-14 1998-01-09 Intermediaires de l'endotheline obtenus par reaction d'addition d'un conjugue asymetrique effectuee au moyen d'un additif chiral
PL98334318A PL334318A1 (en) 1997-01-14 1998-01-09 Method of obtaining intermediate products for use in synthesising antagonists of endotheline by dissymmetrical addition employing a chiral additive
NZ336220A NZ336220A (en) 1997-01-14 1998-01-09 Endothelin intermediates by asymmetric conjugate addition reaction using a chiral additive
BR9806875-0A BR9806875A (pt) 1997-01-14 1998-01-09 Processo para a preparação de um composto.
JP10531063A JP2000507969A (ja) 1997-01-14 1998-01-09 キラル添加剤を用いる非対称コンジュゲート付加反応によるエンドセリン中間体

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US3546297P 1997-01-14 1997-01-14
US60/035,462 1997-01-14
GBGB9705858.0A GB9705858D0 (en) 1997-03-21 1997-03-21 Asymmetric conjugate addition reaction using a chiral additive
GB9705858.0 1997-03-21

Publications (1)

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WO1998030543A1 true WO1998030543A1 (fr) 1998-07-16

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EP (1) EP0973742A1 (fr)
JP (1) JP2000507969A (fr)
KR (1) KR20000070085A (fr)
CN (1) CN1243509A (fr)
AU (1) AU728441B2 (fr)
BR (1) BR9806875A (fr)
CA (1) CA2277161A1 (fr)
EA (1) EA002056B1 (fr)
HR (1) HRP980001A2 (fr)
NZ (1) NZ336220A (fr)
PL (1) PL334318A1 (fr)
SK (1) SK93499A3 (fr)
TW (1) TW432028B (fr)
WO (1) WO1998030543A1 (fr)
YU (1) YU30499A (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6313364B1 (en) 1999-10-28 2001-11-06 Merck & Co., Inc. Synthesis of cyclopropaneacetylene using a catalytic decarboxylation reaction
US6465664B1 (en) 1999-09-15 2002-10-15 Massachusetts Institute Of Technology Asymmetric 1,4-reductions of and 1,4-additions to enoates and related systems
US6552239B1 (en) 1999-10-28 2003-04-22 Merck & Co., Inc. Synthesis of cyclopropaneacetylene by a one-pot process
US7060294B2 (en) 1998-05-27 2006-06-13 Merck & Co., Inc Compressed tablet formulation
US8115032B2 (en) 2009-04-09 2012-02-14 Lonza Ltd. Process for the synthesis of a propargylic alcohol
WO2012048884A1 (fr) 2010-10-14 2012-04-19 Lonza Ltd Procédé de synthèse de carbamates cycliques
WO2012048887A1 (fr) 2010-10-14 2012-04-19 Lonza Ltd Procédé de synthèse de d'alcools propargyliques chiraux cycliques
US8283502B2 (en) 2009-04-09 2012-10-09 Lonza Ltd. Autocatalytic process for the synthesis of chiral propargylic alcohols

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0526708A1 (fr) * 1991-06-13 1993-02-10 F. Hoffmann-La Roche Ag Sulfonamide, sa préparation et son usage comme médicament et intermédiaire
WO1993008799A1 (fr) * 1991-11-05 1993-05-13 Smithkline Beecham Corporation Antagonistes recepteurs de l'endotheline

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0526708A1 (fr) * 1991-06-13 1993-02-10 F. Hoffmann-La Roche Ag Sulfonamide, sa préparation et son usage comme médicament et intermédiaire
WO1993008799A1 (fr) * 1991-11-05 1993-05-13 Smithkline Beecham Corporation Antagonistes recepteurs de l'endotheline

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7060294B2 (en) 1998-05-27 2006-06-13 Merck & Co., Inc Compressed tablet formulation
US7595063B2 (en) 1998-05-27 2009-09-29 Merck & Co., Inc. Compressed tablet formulation
US6465664B1 (en) 1999-09-15 2002-10-15 Massachusetts Institute Of Technology Asymmetric 1,4-reductions of and 1,4-additions to enoates and related systems
US6787655B2 (en) 1999-09-15 2004-09-07 Massachusetts Institute Of Technology Asymmetric 1,4-reductions of and 1,4-additions to enoates and related systems
US6313364B1 (en) 1999-10-28 2001-11-06 Merck & Co., Inc. Synthesis of cyclopropaneacetylene using a catalytic decarboxylation reaction
US6552239B1 (en) 1999-10-28 2003-04-22 Merck & Co., Inc. Synthesis of cyclopropaneacetylene by a one-pot process
US8115032B2 (en) 2009-04-09 2012-02-14 Lonza Ltd. Process for the synthesis of a propargylic alcohol
US8283502B2 (en) 2009-04-09 2012-10-09 Lonza Ltd. Autocatalytic process for the synthesis of chiral propargylic alcohols
WO2012048884A1 (fr) 2010-10-14 2012-04-19 Lonza Ltd Procédé de synthèse de carbamates cycliques
WO2012048887A1 (fr) 2010-10-14 2012-04-19 Lonza Ltd Procédé de synthèse de d'alcools propargyliques chiraux cycliques
EP2447255A1 (fr) 2010-10-14 2012-05-02 Lonza Ltd. Processus de synthèse de carbamates cycliques
EP2447247A1 (fr) 2010-10-14 2012-05-02 Lonza Ltd. Processus pour la synthèse d'alcools propargyliques chiraux
US8957204B2 (en) 2010-10-14 2015-02-17 Lonza Ltd. Process for the synthesis of cyclic carbamates

Also Published As

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PL334318A1 (en) 2000-02-14
CA2277161A1 (fr) 1998-07-16
EA199900661A1 (ru) 2000-02-28
NZ336220A (en) 2000-12-22
HRP980001A2 (en) 1998-10-31
SK93499A3 (en) 2000-05-16
KR20000070085A (ko) 2000-11-25
BR9806875A (pt) 2000-04-18
AU5908998A (en) 1998-08-03
EP0973742A1 (fr) 2000-01-26
CN1243509A (zh) 2000-02-02
AU728441B2 (en) 2001-01-11
TW432028B (en) 2001-05-01
YU30499A (sh) 2002-06-19
JP2000507969A (ja) 2000-06-27
EA002056B1 (ru) 2001-12-24

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